Elderly individuals demonstrate both an increased incidence of influenza morbidity and mortality and a decreased response rate to influenza vaccine. While a hemaglutination inhibition (HI) reciprocal titer of > 40 has been considered protective, reports indicate that in the elderly titers of > 40 may not be sufficient for protection. Further in the young and in mice, cell-mediated immunity (CMI), particularly as demonstrated by cytotoxic T cell (CTC) response, is at least partially responsible for control of influenza infection. Accordingly, the overall goal of this project is to determine the importance of CMI in preventing and/or ameliorating influenza infection in the elderly. In prior studies we have found both that 15% of those > 70 years of age have very low in vitro T cell proliferative response to non-specific mitogens, and 45% do not demonstrate T cell proliferative response to influenza vaccine one month after vaccination. Although a great majority who demonstrate low mitogen responses also have no response to influenza vaccine, many with intact mitogen responses fail to respond to influenza vaccine. There appears to be no strong correlation between proliferative responses to mitogens or influenza vaccine and production of anti-influenza antibodies. The proposed study will: 1) Verify preliminary data that low non-specific mitogen proliferation can be used to predict lack of a proliferative in vitro response to influenza vaccine. 2) Establish duration and constancy of CMI to influenza vaccine. This will allow identification of those subjects with diminished vaccination responses who could benefit from more rigorous immunization schedules. 3) Investigate defects in CMI to influenza vaccine, the phenotypic profile of proliferating cells and the roles of IL-2, IL-4, IL-6, interferon- gamma and cytotoxic T cells. 4) Determine the role of CMI in preventing infection and/or ameliorating clinical influenza. 5) Attempt to enhance CMI and/or antibody response by more rigorous immunization. CMI and antibody titers will be assessed before and after immunization and subjects will be observed during the influenza season for evidence of infection. These studies will identify problems in immunizing the elderly to influenza, a major cause of morbidity and mortality in this increasingly larger portion of the population, and indicate ways of enhancing immunity.